How effective is dentin autograft for socket preservation and implant site preparation: A systematic review protocol.

Background Socket preservation is a surgical procedure aimed at preserving the dimensions of the alveolar bone following tooth extraction. It is performed by filling the extraction socket with bone graft material with or without a barrier membrane. Recently, dentine obtained from extracted teeth has been tried as an autograft for socket preservation. Studies have compared the use of dentin to other bone grafts, however, systematic reviews evaluating the efficacy of dentin for socket preservation are limited. Hence, this systematic review protocol is proposed to generate evidence on the efficacy of dentin as a viable alternative to other bone graft materials for socket preservation. Methods This systematic review protocol was prepared according to the Methodological Expectations of the Cochrane Intervention Reviews (MECIR) guidelines. It will be conducted using the Cochrane Handbook for Systematic Review of Interventions. PubMed, Scopus, Web of Science, EMBASE, Epistemonikos, Cochrane Central, and EBSCO databases and clinical trial registries, will be searched for all randomized controlled trials (RCTs) and non-randomized studies that have used autologous dentin graft (either in particulate/putty, or/matrix form) for socket preservation. The radiographic and clinical assessment of bone and soft tissue healing of the preserved sockets along with patient-related outcomes following surgery will be assessed. The risk of bias assessment of the RCTs and Non-RCTs will be assessed using the ‘Cochrane Risk of Bias assessment tool (ROB II) and ROBINS-I respectively. The certainty of evidence will be assessed by the GRADE approach. Discussion This evidence is important for dental clinicians and the public to make an informed decision when choosing graft material for socket preservation. The extracted teeth are considered biological waste; however, this evidence provides scope for using a less invasive autograft for bone regenerative procedures. Systematic review registration PROSPERO: CRD42021201958 (Registered on 15/02/2021).


Introduction
Dental implants are increasingly being used as a promising modality for replacing missing teeth with superior biological, functional, and aesthetic properties. 1 However, one of the important requirements for placing implants is the presence of favorable volume and architecture of the available bone at the time of placement.][4][5] Approximately 29 to 63% of horizontal bone loss and 11 to 22% of vertical bone loss occur within the first six months following tooth extraction. 6[17][18][19][20][21][22][23][24] Sockets can be preserved with either an autograft, xenograft, allograft, or alloplasts.1][22] Autografts can be harvested from edentulous ridges, extraction sockets, mandibular ramus, symphysis, maxillary tuberosity, tibia, iliac crest, and calvarium. 20However, procuring autograft is difficult and requires superior clinical skills.1][22][23][24] To overcome these limitations novel bone graft materials with osteogenic potential are being researched.

REVISED Amendments from Version 1
The new version contains the following changes: 1.As suggested by the reviewers, the inclusion of studies where implants are placed in patients with medically compromised conditions (such as Diabetes) or smokers has been mentioned in the eligibility criteria.2. The year of published articles (2000 and above) to be included in the review has been added.3. We have also included the subgroup analysis which can be performed based on the age, gender, systemic/medical condition of the patient, and clinical condition of the site of socket preservation.
6][27][28][29] It is available in three forms: demineralized dentin matrix, partially demineralized dentin matrix, and un-demineralized dentin.7][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42] However, there are still various uncertainties and limited systematic reviews related to its use for socket preservation compared to other bone graft materials.The PubMed search with the keyword dentin bone graft yielded only six systematic reviews, with none comparing dentin to other bone graft materials for socket preservation.There is limited data that quantitatively substantiate whether sockets preserved with dentin bone graft are better than those preserved with other bone graft material.Additionally, the understanding of the effect of dentin bone graft on the nature of bone healing and soft tissue healing around the preserved sockets, stability of implants placed in the sockets preserved with dentin, and postoperative complications after using dentin are limited.Thus, this systematic review aims to synthesize evidence on the effectiveness and efficacy of dentin autograft as a graft material for socket preservation compared to allograft, alloplast, and xenograft materials.This evidence is crucial for clinicians, patients, and other stakeholder groups in making evidence-based choices regarding the use of dentin as a bone graft material.

Focus question
How effective is dentin autograft compared to other bone graft material (autograft, allograft, xenograft, and alloplast) for socket preservation?

Primary objective
To assess the clinical and radiographic changes in the height and width (in mm) of the extraction sockets preserved with dentin autograft (particulate/putty) compared to allograft, alloplast, and xenograft materials.
Secondary objectives 1.To evaluate and compare the clinical and radiographic change in the quality of bone and soft tissue healing in sockets preserved with dentin bone graft compared to sockets preserved with other bone grafts (allograft, alloplast, or xenograft).
2. To assess and compare the details of the type of dentin bone graft used, method of application, duration of surgical procedure, patient's compliance, and time of surgery with dentin bone graft compared to sockets preserved with other bone graft (allograft, alloplast or xenograft).
3. To assess and report prognosis and any adverse events/effects or postoperative complications associated with the use of dentin autografts for sockets preservation.

Methods
The proposed systematic review will be conducted according to the Cochrane Handbook for the Systematic Review of Interventions, 43 Methodological Expectations of the Cochrane Intervention Reviews (MECIR) guidelines 44 and the Preferred Reporting Items for Systematic Review and Meta-analysis Protocols (PRISMA-P) checklist. 45,48The systematic review protocol has been registered in the International Prospective Register of Systematic Review PROSPERO with registration number -CRD42021201958 on 15/02/2021.Differences between the protocol and the final review, if any, because of the methodological alterations due to the unavailability of data, will be reported in the final review.
Criteria for considering studies for the proposed systematic review The eligibility criteria are described using the Participant-Intervention-Comparison-Outcome-Study Design (PICOS) framework, which also indicates the key components of the research question.

Types of participants
For the proposed systematic review, studies with participants who are above 18 years of age and have undergone a socket preservation procedure following tooth extraction will be included.Any studies where implants were placed in patients with systemic diseases such as controlled diabetes, smokers, and cardiovascular, renal, respiratory, and neurological disorders, etc. will be included.
Studies with participants who have or have not received any dental implants, either at the time of socket preservation or following socket preservation will also be included.Participants who have undergone tooth extraction because of any of the following reasons will be included: unrestorable tooth due to caries or fracture; avulsion of a tooth following trauma; root resorption (internal or external); tooth fracture that cannot be restored; endodontic infection or periodontal disease that cannot be addressed with endodontic and periodontal therapy; failure of root canal treatment, a tooth with grade III mobility and more than 50% bone loss, Grade IV furcation defect (based on Glickman classification) with through and through bone defect that cannot be regenerated and needs an extraction.
Following exclusion criteria will be followed: 1. Studies with participants suffering from conditions or diseases that might impair bone healing or metabolism, for example, osteoporosis, vitamin D deficiency, and use of anti-resorptive therapy such as bisphosphonates.
2. Studies with participants who use tobacco products, areca nut, gutka, or supari, as smoking.The above factors may influence the uptake of the graft material and or dental implants and hence have been used as exclusion criteria.
3. Studies with participants undergoing chemotherapy or radiation therapy as these treatment modalities compromise angiogenesis and impair bone healing.

Types of interventions
Studies, where the extraction sockets are preserved with any form of dentin bone graft (demineralized, partially demineralized, or not demineralized) in any form (particulate/putty/matrix/gel), size, or application method with or without a barrier membrane will be included.Studies, where the extraction sockets are preserved with dentin (any particle size) and compared to other bone grafts such as other autografts, alloplasts, allografts, and xenografts with a minimum follow-up of three months will be included.Since bone healing requires a minimum of three months, studies providing a three-month follow-up will be included.Studies where implants are placed immediately following socket preservation will also be included.Studies with both infected and non-infected sockets will be included.Studies where the whole tooth was used as a graft material, will not be considered.

Types of outcomes
The following outcomes will be considered in the proposed review: 1) Clinical and radiographic changes in the height and width (in mm) of the socket before and after socket preservation with dentin bone graft compared to other bone graft; 2) Changes in quality of bone following socket preservation; 3) clinical assessment of soft tissue (in terms of gain in the width of keratinized gingiva) following socket preservation; 4) details of the type of dentin bone graft used, method of application, duration of surgical procedure 5) occurrence of any immediate and delayed post-operative complications following socket preservation surgery.

Types of studies
In the proposed systematic review, randomized controlled trials (RCTs), the gold standard study design for assessing the effectiveness of an intervention will be used as the preferred study design for inclusion.RCTs with parallel-group, individual participant, or cluster-allocation designs comparing the independent effects of the intervention on the comparison group will all be included.Non-randomized trials such as pre-post (controlled before-after) and quasiexperimental studies will also be included.Case series with more than 10 subjects and a follow of at least three months would be included.Animal studies, case series with fewer than 10 subjects, letters to the editor, and case reports will all be excluded from inclusion.The proposed systematic review will only include manuscripts published in English and published in 2000 or later.

Context or setting
Studies conducted in hospitals, dental clinics, university hospitals, and other relevant healthcare facilities, dependent on the country where the study was conducted, will be included in the review.Studies, where treatment was provided by specialists and non-specialists, will be included in the review.

Search strategy and information sources
A search strategy was developed using keywords identified from the preliminary search and following agreement between the research team (KS, AC, ER) and a search expert (GC, BK).It included Medical Subject Headings (Mesh) terms, free text terms, and Boolean (AND, OR), as well as the components of the PICO framework.The advanced search strategy for PubMed, one of the databases to be searched is given in Table 1.An electronic search for English language publications in PubMed, Scopus, Web of Science, EMBASE, Epistemonikos, EBSCO (Dentistry and Open Access), and Cochrane CENTRAL databases will be conducted.Additionally, ProQuest, World Clinical Trial Registry, and Clinical Trials Registry of India (CTRI) will be searched for ongoing clinical trials.The corresponding authors for the ongoing clinical trials will be requested to share the results (if available).In addition, the bibliography section of the following journals will be searched for any articles in press: Journal of Periodontology, Journal of Dental Research, Journal of Periodontal Research, Journal of Clinical Periodontology, Journal of Clinical Oral Implant Research, Journal of Implantology, Journal of Clinical Implants and Related Research.We will also check references of the included studies for other relevant articles.Preprint servers such as BioRxiv, Research Square, and MedRxiv will be screened for relevant articles on dentin as bone graft material used in socket preservation.Doctoral theses, conference proceedings, and industry studies published in company publications will also be screened for relevant literature.

Study selection (screening process)
The search results will be managed using the Microsoft Office (MS) Excel software.After the removal of duplicates, four reviewers (KS, AC, SM, ND) will independently select studies using the inclusion and exclusion criteria.The screening process will be performed in two stages.In the first stage, the titles, and abstracts of the studies will be independently screened.Studies that do not qualify according to the eligibility criteria and those with inadequate data or information will be excluded at the title/abstract (Ti/Ab) screening stage.In the second stage, full-text screening of the included studies will be performed independently by the four reviewers (KS, AC, SM, ND).They will also perform hand-searching of the journals listed above and screen the potential articles for inclusion.Any disagreements regarding inclusion will be resolved initially by discussion between the reviewers (GC) and if unresolved the other reviewers (BK, KS) will be consulted for agreement; a majority decision will be adopted.A pre-designed screening protocol will be used to select studies (Table 2).Data extraction Three reviewers (KS, AC, ND, SM) will perform data extraction independently, using a pre-designed pilot-tested data extraction sheet.Any disagreements during the extraction process will be resolved initially by discussion between three reviewers, and if still unresolved BK and GC will be consulted.A majority decision will be adopted as final.In case of unpublished and missing information/data, the study authors will be contacted to request the required information.
If adequate data are available, the review team will perform additional relevant statistical analysis.

Outcomes assessed
The outcomes considered in the proposed review are: i. Clinical and radiographic assessment of the overall bone volume gain or otherwise, following socket preservation as measured by the gain or otherwise, in the mesiodistal, buccolingual, and apicocoronal dimensions of the socket before and after the intervention (in mm) will be measured.This can be measured by bone-sounding/ trans-gingival probing or any radiographic assessment.The changes in the proximal/interdental bone levels at teeth-bounding extraction sites will also be noted.
ii.The nature of bone, and quality of bone as assessed by any clinical or radiographic method will be considered.Radiographic assessment of bone volume or quality as measured by changes in the density of the trabecular pattern (no/mm 2 ); changes in the trabecular pattern; ratio of cortical to cancellous bone in terms of Hounsfield unit (HU) in the extraction socket pre-and post-intervention (mm 2 ); or any other techniques reported in respective studies will be considered.The stability of implants in sockets preserved with dentin bone graft compared to other bone grafts is of interest.
If the clinical method is not used and the radiographic method is used in the studies to provide the change in the dimension of the socket and it does not provide three-dimensional information, the two-dimensional measurement will be recorded.
The method of assessment will also be recorded.These outcomes have been chosen as the primary outcomes because the quality and quantity of bone and soft tissue following socket preservation are the most crucial outcomes to define success.
Secondary outcomes: i.The health of soft tissue around the socket preserved, as measured by the health of the gingival tissues, and gain in the amount of keratinized tissue after socket preservation at baseline and post-treatment, as measured by any histomorphometric analysis or manually by any periodontal probe will be noted.
ii.The percentage/amount of bone graft remaining in the socket post-intervention (at each recall) reported by surgical re-entry, histology, or radiographic imaging technique will be considered.
iii.The presence or absence of any postoperative complications at the time of surgery, immediately after surgery; within 24 hours, or delayed after socket preservation will be considered.Presence or absence of non-healed sockets, delayed socket healing, exposure of barrier membrane, loss of graft material, presence and presence of soft tissue defects on the alveolar ridge; presence or absence of any suppuration, pus discharge, excessive bleeding, dehiscence and opening of the wound, fenestration on the buccal or lingual aspect of the closed wound, recession of soft tissue following surgery, postoperative pain, persistent pain or dysesthesia following treatment as measured by any pain scale such as Visual Analog Scale (VAS), Numeric Rating Scale (NRS), and The Wong-Baker face pain scale following socket preservation are other will be considered.
iv.Time required between socket preservation and implant placement; nature of osseointegration if implants were placed at the time of socket preservation will be considered.
v. Health of the tooth used for procurement of dentin; type of dentine used, method of processing of dentin; time of utilization of tooth following extraction; method of storage of dentin, mode of application of dentin (with or without any device) and particle size of dentin graft (if mentioned); use of dentin with or without a barrier membrane will be considered.

Risk of bias (ROB) assessment
The risk of bias will be assessed using the revised Cochrane Risk of Bias Assessment Tool (ROB2). 46,47Two review authors (KS, AC) will independently assess the risk of bias in the included studies.Any disagreements will be resolved via discussion, if consensus cannot be reached, then a majority decision will be adopted after consulting the other two reviewers (BK, GC).The following domains will be assessed for risk of bias: 1. Randomization process; 2. Bias resulting from deviations from intended interventions; 3. Bias resulting from missing outcome data; 4. Bias resulting from measurement of the outcome; 5. Bias resulting from selection of the reported result; 6. Bias in the identification or recruitment of individual participants within clusters.If cluster-RCTs are included, whether the reported data analysis had appropriately taken account of the aggregate nature of the data will be determined.The identified risks shall be categorized as low risk, high risk, and risk with some concern.The 'effects of assignment' will be considered as the effect of principal interest to assess the risk of bias.
Quality assessment of non-randomized studies will be performed using the Risk of Bias In Non-Randomized Studies of Interventions (ROBINS-I). 47As per this tool, bias in a non-randomized trial will be assessed for the following seven domains: 1) Bias due to confounding, 2) Bias in the selection of participants into the study, 3) Bias in the classification of interventions, 4) Bias due to deviations from intended interventions, 5) Bias due to missing data, 6) Bias in measurement of outcomes, 7) Bias in selection of the reported result.The assessed risk will be categorized as low risk, moderate risk, serious risk, and critical risk.

Measures of effects
In the case of continuous data, Mean Difference (MD) and Standard Mean Difference (SMD) with 95% Confidence Interval (CI) will be used to estimate the effects of the intervention.Odds Ratio (OR) and Risk Ratio (RR) with 95% CI will be used for categorical data.

Unit of analysis
The participant will be the unit of analysis for individual randomized trials, however, a study cluster will be considered as the unit of analysis for cluster-randomized trials.The impact of data clustering will be considered and the unit of analysis will be adjusted accordingly during analysis.

Data synthesis
Meta-analysis will be performed in case homogenous data is obtained from the included studies.I 2 statistic will be used to assess statistical heterogeneity, describing the percentage of the variability in effect estimates that is due to heterogeneity rather than chance.Based on the I 2 statistic, the level of heterogeneity will be categorized as follows: • 0% to 40%: might not be important • 30% to 60%: may represent moderate heterogeneity • 50% to 90%: may represent substantial heterogeneity • 75% to 100%: considerable heterogeneity A fixed-effects model will be used for meta-analysis.A forest plot will be used to report the results of the meta-analysis.
A narrative synthesis, with tables and figures for explanation, will be performed when meta-analysis is not possible in case of more than 50% 'clinical,' 'methodological,' and 'statistical' heterogeneity.

Sub-group analysis
If possible, sub-group analysis will be performed based on the height and width of the socket before and after socket preservation; quality of bone formed before and after socket preservation in dentin compared to other bone grafts; nature of soft tissue before and after socket preservation in dentin compared to other bone graft; post-operative complications following socket preservation.The comparison of healing of sockets in healthy patients compared to those with the systemic condition will done (based on the article retrieved).The comparison of healing based on age and gender analysis can also be analysed.

Assessment of reporting bias
Funnel plots will be used for the identification of reporting bias.The identification of reporting bias will be done based on the visual assessment of the funnel plot, where a symmetrical funnel plot will be interpreted as the absence of reporting bias and an asymmetrical plot will indicate the presence of reporting bias.

Sensitivity analysis
If sufficient data is available, a sensitivity analysis will be performed to assess the robustness of the results.This will be done using studies with a 'low risk of bias'.

Assessment of certainty of evidence
The certainty of evidence will be assessed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach.This approach grades evidence for five domains 1) risk of bias, 2) indirectness, 3) inconsistency, 4) imprecision, and 5) publication bias.The level of certainty of evidence will be classified as high, moderate, low, and very low, using the GRADE Pro GDT software, independently by three of the review authors (KS, AC, and ER).Disagreements will be resolved by discussion and in case of non-consensus, the two other authors (BK and GC) will be consulted, and a majority decision taken.The certainty of evidence will be reported for the following seven outcomes 1) Changes in the dimensions (height and width) of the alveolar ridge following grafting; 2) Nature of bone and soft tissue healing following socket preservation; 3) Postoperative complications (presence and absence of pain, dysesthesia, suppuration, marginal bone loss or loss of graft material.

Study status
The review is currently in the full-text screening stage.

Discussion
The proposed systematic review will assess the quality of the evidence base available regarding the efficacy and efficiency of using dentine bone graft material in socket preservation.The review will help to understand whether dentin has a superior osteogenic potential than other bone grafts and what future complications one should note when using dentin.9][20] Since many times the tooth is discarded as a biological waste, the utilization of the same tooth for regeneration of bone defect would preclude the need for additional bone graft material.This would help patients to obtain a cheaper, affordable, and relatively easier option compared to other autografts.4][25][26][27][28][29][30][31][32] We have involved relevant stakeholders such as clinicians, patients, and researchers for the identification of research uncertainties and the formulation of the research question.After consultation with the stakeholders, the need for a non-invasive, cheaper, and more comfortable option for procuring autografts was deemed necessary.We also took feedback from patients in our clinics regarding their experience following surgery where autograft was procured from the chin and ramus.There is a need to explore this research knowledge and explore the efficacy of dentin as bone graft material for socket preservation and at the same it is important to understand the clinical outcomes and patient-related outcomes after surgery using dentin as a bone graft material.The review will also cue the dentist to understand the probable complications associated with dentin bone graft.Thus, the comprehensive evaluation of research and the resulting consolidated up-to-date evidence will help clinicians make evidence-informed decisions while choosing graft material.Additionally, the review will also propose further studies required to address gaps identified in the knowledge created so far on dentine as a graft material.It is hoped that collaborative research with clinicians, scientists, and the industry will be promoted as a result of the planned review.However, one should note that one of the limitations of the proposed review is that the evidence will be based on English language literature only.Although this review aims to explore, the role of dentin as graft material for socket preservation, we would not be able to provide strong evidence on the stability, prognosis, and long-term survival of the implants as these factors have many confounding variables that cannot be addressed and is not within the scope of this review.However, future studies should explore the prognosis and survival rate of implants in sockets preserved in the dentin compared to other bone grafts.

Underlying data
No data are associated with this article.

Reporting guidelines
Figshare: PRISMA-P checklist for 'How effective is dentin autograft for socket preservation and implant site preparation: A systematic review protocol.'https://doi.org/10.6084/m9.figshare.25195910. 48ta are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).

Marwa Madi
Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia The study is well written and the methodology is explained in a detailed and organized manner.Since the objective of the review is clinical and radiographic findings as well as soft tissue healing following socket preservation using dentin allograft I think the authors need to exclude all animal studies and include only clinical studies.

Strength of the proposal:
The proposal addresses a novel approach by investigating the use of dentin autografts for socket preservation, which is an emerging area in dental research.This originality is relevant and significant for students at this level.The proposal is grounded in a well-established scientific premise, highlighting the importance of alveolar ridge preservation and the potential benefits of using dentin as a graft material.The background information provided is comprehensive and supports the rationale for the study.The benefits of publishing with F1000Research: Your article is published within days, with no editorial bias • You can publish traditional articles, null/negative results, case reports, data notes and more • The peer review process is transparent and collaborative • Your article is indexed in PubMed after passing peer review • Dedicated customer support at every stage • For pre-submission enquiries, contact research@f1000.com

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The methodology is robust, following the Cochrane Handbook for Systematic Reviews and adhering to PRISMA-P guidelines.The use of multiple databases for literature search, clear inclusion and exclusion criteria, and detailed data extraction and analysis plan demonstrate feasibility and rigor.○Theweakness of the proposal: Focus on Specific Population:The study focuses on healthy adults, potentially overlooking how dentin autografts might perform in populations with comorbidities or different age groups.○Limited Scope of Comparative Studies: While the proposal compares dentin autografts with other types of grafts, it does not account for potential variations in outcomes based on patient demographics or specific clinical conditions.Is the rationale for, and objectives of, the study clearly described?YesIs the study design appropriate for the research question?YesAre sufficient details of the methods provided to allow replication by others?YesAre the datasets clearly presented in a useable and accessible format?YesCompeting Interests: No competing interests were disclosed.Reviewer Expertise: Periodontology; implant dentistry I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.